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COAGULATION CORNER: SEPTEMBER 2011

An unusual cause for a prolonged APTT: 

A 65 year old male patient being screened pre-operatively is tested for PT, APTT, fibrinogen and a Factor VIII. Previously, having had bloods drawn for hernia surgery, he was told that he had a prolonged APTT and was diagnosed a moderate hemophiliac. He was sent to have a hemophilia work up. Results were as follows:

PT = 11.2 seconds
APTT= 98.5 seconds
Fibrinogen = 300 mg/dL
FVIII = 52%
vWF activity = 68%
vWF antigen=72% 

Based on a normal fibrinogen, FVIII, and vW work up, additional testing was performed:

FIX = 92%
FXI =103%
FXII=3% 

Diagnosis:  Factor XII deficiency 

Factor XII deficiency is a congenital disorder that is most commonly inherited as an autosomal recessive trait and is not associated with a bleeding diathesis.  Easy bruising and epistaxis has been reported in an occasional FXII deficient patient. 

Factor XII deficiency is the most common cause of an isolated prolongation of the APTT in a non-bleeding child or adult.  Most patients are diagnosed as part of a pre-operative screen.  Bleeding

The incidence of prolonged screening tests are as follows:

FXII is a single chain beta-globulin serine protease with a molecular weight of 80-84,000 daltons.  Factor XII is a coagulation protein which is either autoactivated by contact with a number of artificial or biologic negatively charged surfaces (contact activation) or by proteolytic activation on the surface of endothelial cells by prekallikrein/kallikrein and high molecular weight kininogen. Cleavage is mediated by charged surfaces (glass, kaolin, celite, dextran sulfate, endotoxin, urates, crude collagen, and sufatides.  Activated factor XII converts prekallikrein to kallikrein (which activates more factor XII, liberates bradykinin from high molecular weight kininogen, and activates complement components C3 and C5), activates factor XI which eventually leads to thrombin generation via the intrinsic pathway, and also activates C1 esterase, thereby activating the complement system. 

Factor XII deficiency has been reported to be a risk factor for the development of arterial and venous thromboembolism. The first patient discovered to have a FXII deficiency was John Hageman who died of a PE. Hence the name Hageman factor.  A high incidence of strokes, DVT, MI have been described in this cohort of patients at a rate of 1-8%.   Heterozygous individuals have factor XII levels between 20-60%.  Homozygotes or double heterozygotes have levels < 0.01%. 

In a study that looked at the normal population, of about 300 healthy blood donors seven FXII deficiencies were detected. On the basis of these data the prevalence of severe and mild FXII deficiency in the normal population can be estimated to be 1.5-3.0%. Assessment of FXII antigen levels revealed, that all seven FXII deficient individuals had FXII antigen levels matching the activity. One presented a severe FXII deficiency (1/300, 0.3%) without detectable FXII activity and an APTT prolongation of more than 120 s. 

Acquired FXII is seen in nephritic syndrome, endotoxin-induced sepsis and shock, DIC, respiratory distress, polycythemia vera, hepatic cirrhosis and other diseases.  A spontaneous increase in FXII occurs in pregnancy and with the use of oral contraceptives. 

Activated Factor XII (FXIIa)

Contact activation of negatively charged surfaces which activate FXII affects several pathophysiological processes including hypotension, inflammation, thrombosis and fibrinolysis. Studies have demonstrated a relationship between XIIa and  an increased risk of coronary heart disease.  Additionally XIIa measured after an MI predicts recurrent coronary occlusive events and Is an independent marker in these patients. It has been recently discovered that FXII exsists in different forms.  One of those forms, XIIaA was evaluated to access the long term prognosis of chest pain individuals.  It was demonstrated that these levels are predictive of long term mortality and may aid in the risk assessment of patients with acute coronary syndrome and my be of greater value in unstable patients with coronary heart disease.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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